U.S. patent number 8,399,443 [Application Number 12/765,708] was granted by the patent office on 2013-03-19 for treatment of hypertension by renal vascular delivery of guanethidine.
This patent grant is currently assigned to Mercator Medsystems, Inc.. The grantee listed for this patent is Kirk Patrick Seward. Invention is credited to Kirk Patrick Seward.
United States Patent |
8,399,443 |
Seward |
March 19, 2013 |
Treatment of hypertension by renal vascular delivery of
guanethidine
Abstract
Sympathetic nerves run through the adventitia surrounding renal
arteries and are critical in the modulation of systemic
hypertension. Hyperactivity of these nerves can cause renal
hypertension, a disease prevalent in 30-40% of the adult
population. Hypertension can be treated with neuromodulating agents
(such as angiotensin converting enzyme inhibitors, angiotensin II
inhibitors, or aldosterone receptor blockers), but requires
adherence to strict regimens and often does not reach target blood
pressure threshold to reduce risk of major cardiovascular events. A
minimally invasive solution is presented here to reduce the
activity of the sympathetic nerves surrounding the renal artery by
locally delivering neurotoxic or sympathetic nerve-blocking agents
into the adventitia. Extended elution of these agents may also be
accomplished in order to tailor the therapy to the patient.
Inventors: |
Seward; Kirk Patrick (San
Francisco, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Seward; Kirk Patrick |
San Francisco |
CA |
US |
|
|
Assignee: |
Mercator Medsystems, Inc. (San
Leandro, CA)
|
Family
ID: |
43011483 |
Appl.
No.: |
12/765,708 |
Filed: |
April 22, 2010 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20110104060 A1 |
May 5, 2011 |
|
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
61186704 |
Jun 12, 2009 |
|
|
|
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61171702 |
Apr 22, 2009 |
|
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Current U.S.
Class: |
514/183 |
Current CPC
Class: |
A61P
9/12 (20180101); A61M 25/0084 (20130101); A61M
25/00 (20130101); A61K 31/395 (20130101); A61M
5/007 (20130101); A61P 9/00 (20180101); A61M
5/44 (20130101); A61K 31/155 (20130101); A61K
45/06 (20130101); A61M 5/00 (20130101); A61K
9/0019 (20130101); A61M 25/1002 (20130101); A61K
31/155 (20130101); A61K 2300/00 (20130101); A61M
2025/009 (20130101) |
Current International
Class: |
A01N
43/00 (20060101); A61K 31/33 (20060101) |
Field of
Search: |
;514/183 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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05-293176 |
|
Nov 1993 |
|
JP |
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11-262527 |
|
Sep 1999 |
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JP |
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2003-000708 |
|
Jan 2003 |
|
JP |
|
WO 99/33504 |
|
Jul 1999 |
|
WO |
|
WO 02/100459 |
|
Dec 2002 |
|
WO |
|
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|
Primary Examiner: Sznaidman; Marcos
Attorney, Agent or Firm: Wilson, Sonsini, Goodrich &
Rosati
Parent Case Text
CROSS-REFERENCES TO RELATED APPLICATIONS
This application claims the benefit of prior provisional
applications 61/171,702, filed on Apr. 22, 2009; and 61/186,704,
filed on Jun. 12, 2009. The full disclosures of each of these prior
provisional applications are incorporated herein by reference.
Claims
I claim:
1. A method for treating hypertension in a patient, said method
comprising the delivering of an amount of guanethidine to the
nerves surrounding a blood vessel, wherein delivery comprises
injecting guanethidine into tissue bound on the inside by the
external elastic lamina of said blood vessel and bound on the
outside by the outer extent of the adventitial and perivascular
connective tissues that surround the blood vessel, wherein the
amount is effective to lower systemic blood pressure by a
therapeutically beneficial amount.
2. A method as in claim 1, wherein delivery includes a step of
positioning a needle through the wall of a target blood vessel so
that an aperture of the needle is positioned beyond an external
elastic lamina (EEL) of the wall.
3. A method as in claim 1, wherein delivery further includes a step
of confirming that said guanethidine is penetrating said tissue by
imaging either the guanethidine mixed with a diagnostic agent or by
the delivery of a diagnostic agent prior to the delivery of the
guanethidine.
4. A method as in claim 1, wherein the blood vessel is an
artery.
5. A method as in claim 4, wherein the artery is a renal
artery.
6. A method as in claim 5, wherein delivery comprises delivering
the guanethidine to both of the patient's renal arteries.
7. A method as in claim 1, wherein the blood vessel is a vein.
8. A method as in claim 7, wherein the vein is a renal vein.
9. A method as in claim 8, wherein delivery comprises delivering
the guanethidine to both of the patient's renal veins.
10. A method as in claim 1, wherein the guanethidine is delivered
in a dosage of from 10 .mu.g to 100 mg.
11. A method as in claim 10, wherein the dosage is in the range
from 50 .mu.g to 50 mg.
12. A method as in claim 11, wherein the dosage is in the range
from 100 .mu.g to 30 mg.
13. The method of claim 1, comprising injecting the amount of
guanethidine through a wall of the blood vessel.
14. The method of claim 10, wherein the dosage is the amount in
total that is delivered to the patient.
15. The method of claim 10, wherein one delivery of the dosage is
effective to lower systemic blood pressure by a therapeutically
beneficial amount.
16. The method of claim 5, wherein the delivery is performed
between the aorta and the hilum of the kidney.
17. The method of claim 5, wherein the delivery is performed along
the renal artery to the nerves which terminate in the kidney.
18. The method of claim 1, wherein patient is human.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to medical devices,
systems, and methods to treat disease. More particularly, the
present invention relates to methods to treat hypertension by
delivering guanethidine to reduce hyperactive sympathetic nerve
activity in the adventitia of arteries and/or veins that lead to
the kidneys.
Hypertension, or high blood pressure, affects an estimated 30-40%
of the world's adult population. Renal, or renovascular,
hypertension can be caused by hypoperfusion of the kidneys due to a
narrowing of the renal arteries. The kidneys respond by giving off
hormones that signal the body to retain salt and water, causing the
blood pressure to rise. The renal arteries may narrow due to
arterial injury or atherosclerosis. Despite effective drug regimens
to regulate the renin-angiotensin-aldosterone pathway or to remove
excess fluid from the body and reduce blood pressure, some 20-30%
of patients with hypertension suffer from resistant forms of the
disease.
Resistant hypertension is a common clinical problem, caused when a
patient is unable to control high blood pressure by medication
alone. Resistant hypertension is especially a problem in old and
obese people. Both of these demographics are growing. While
symptoms are not obvious in these patients, cardiovascular risk is
greatly increased when they are unable to control their blood
pressure.
Hypertension is also caused by hyperactive renal sympathetic
nerves. Renal sympathetic efferent and afferent nerves run
generally longitudinally along the outside of arteries leading from
the aorta to the kidneys. These nerves are critically important in
the initiation and maintenance of systemic hypertension. It has
been shown that by severing these nerves, blood pressure can be
reduced. Exemplary experiments have shown that denervation of the
renal sympathetic nerves in rats with hyperinsulinimia-induced
hypertension would reduce the blood pressure to normotensive levels
as compared to controls [Huang W-C, et al. Hypertension 1998;
32:249-254].
Percutaneous or endoscopic interventional procedures are very
common in the United States and other countries around the world.
Intravascular catheter systems are used for procedures such as
balloon angioplasty, stent placement, atherectomy, retrieval of
blood clots, photodynamic therapy, and drug delivery. All of these
procedures involve the placement of long, slender tubes known as
catheters into arteries, veins, or other lumens of the body in
order to provide access to the deep recesses of the body without
the necessity of open surgery.
In cases where renal arterial occlusion is causing hypertension
that cannot be controlled with medication, another potential
therapy includes balloon angioplasty of the renal artery. In rare
cases, surgical bypass grafting may be considered as a therapeutic
alternative. While renal angioplasty can be effective in reducing
blood pressure, angioplasty is plagued with resulting restenosis
due to elastic recoil, dissection, and neointimal hyperplasia.
Renal stents may improve the result, but also lead to restenosis or
renarrowing of the artery due to neointimal hyperplasia.
While renal denervation had been performed with surgical methods in
the past, more recently a catheter-based therapy to heat and
destroy the nerves from within the renal artery using
radio-frequency ablation has been studied. A human trial of the
RF-ablation catheter method has also been performed, with reported
reduction in blood pressure in patients enrolled in the catheter
treatment arm of the study [Krum H, et al. Lancet 2009;
373(9671):1228-1230].
While the use of catheter-based radiofrequency (RF) denervation
appears to have a therapeutic effect, it is unknown what long-term
implications will arise from the permanent damage caused to the
vessel wall and nerves by the RF procedure. Radiofrequency energy
denervates the vessel by creating heat in the vessel wall. The RF
probe contacts the inner lining of the artery and the RF energy is
transmitted through the tissue.
Anti-hypertension therapies can be problematic in a number of
respects. First, hypertension is, for the most part, an
asymptomatic disease. Patients can lack compliance to medicinal
regimens due to their perceived lack of symptoms. Second, even for
patients that are highly compliant to drug therapy, their target
blood pressure may not be reached, with little to no recourse but
for intervention. Third, when intervention is taken (usually in the
form of renal angioplasty and/or stenting), the long-term effects
can include restenosis, progression of chronic kidney disease, and
ultimately kidney failure, because angioplasty leads to activation
of an injury cascade that causes fibrosis and remodeling of the
target artery. Fourth, surgical techniques to bypass or denervate
renal arteries are radical and can lead to a number of surgical
complications. And fifth, it is unknown whether RF denervation of
the artery will lead to further exacerbation of stenotic plaques,
whether it is compatible with arteries in which stents have been
placed, whether the energy transmission through thick plaques or
fibrous intima will be enough to effect the underlying nerves
procedure will work if the RF probe is in contact with a thick
plaque in the majority of patients, or whether the effective
deadening of not only nerves, but the smooth muscle in the arterial
wall also, may lead to reactive hypervascular formation of the vasa
vasorum and necrotizing plaques that, if ruptured, would result in
acute kidney ischemia or chronic kidney disease. Thus, systems and
protocols which are designed to produce sympathetic denervation
with RF energy or surgical dissection are limited in their
applicability across the breadth of hypertensive disease, or they
may create new vascular complications that were not inherent to the
underlying disease.
Current antihypertensive drugs typically modulate blood pressure by
interrupting the renin-angiotensin-aldosterone axis or by acting as
a diuretic. An earlier generation of antihypertensive agents had
modes of action to directly impair the renal nervous system. Agents
like guanethidine, guanacline, and bretylium tosylate would
modulate hypertension by preventing release of norepinephrine (also
known as noradrenaline) from sympathetic nerve terminals. With
guanethidine, sympathectomy accomplished by interfering with
excitatory vesicular release and by replacing norepinephrine in
synaptic vesicles. Sympathetic nerve failure has been previously
demonstrated in rats and hamsters, but not humans, possibly because
guanethidine was typically delivered systemically and the high
local concentrations required to induce sympathetic denervation in
humans would come at the risk of extremely undesirable systemic
side effects. The use of guanethidine to create functional
denervation in rodents is considered permanent, with no evidence of
reinnervation of tissues for as long as 63 weeks after treatment in
rats. In high doses, guanethidine inhibits mitochondrial
respiration and leads to neuron death. Importantly for this
invention, guanethidine can be used to create local denervation in
a dose-dependent manner and without far-field effects. This has
been seen in an experiment comparing guanethidine injection into
one hindquarter of a hamster and compared to a control injection on
the contralateral side, performed by Demas and Bartness, J Neurosci
Methods 2001. This is an advantage for the use of the agent to
localize the effect to a specific renal artery without diffusion
beyond the renal sympathetic ganglion to the spinal cord or other
nervous systems. Also of interest to this invention is the
published observation that guanethidine selectively destroys
postganglionic noradrenergic neurons (thus reducing norepinephrine)
while sparing dopaminergic fibers and normeural
catecholamine-secreting cells. It is this high level of specificity
for which guanethidine has been chosen as a useful therapy.
Finally, guanethidine was approved by FDA for use as a systemic
antihypertensive agent due to its ability to block sympathetic
function, but has not been approved for local administration to
cause long-term or permanent denervation.
Locally delivered guanethidine has produced localized sympathectomy
in hamster hindquarters, as observed by Demas and Bartness, 2001.
In a series of 10 to 20 unilateral injections of 2 microliters each
containing 5 to 10 micrograms of guanethidine per microliter, into
the inguinal adipose tissue of hamsters, compared to similar
injections of placebo into the contralateral inguinal adipose
tissue, functional sympathectomy of one side versus the other was
seen with at least 200 micrograms of delivery, whether spread
across 10 or 20 injections of 2 microliters each. The result was
determined in this case by measuring the norepinephrine content of
the tissue 2 weeks after delivery, with substantial reduction in
the side that had received guanethidine versus the control
(placebo) side.
Guanethidine has the chemical name Guanidine,
[2-(hexahydro-1(2H)-azocinyl)ethyl]-, and is often supplied in the
sulfate form, guanethidine sulfate or guanethidine monosulfate (CAS
645-43-2) with chemical name Guanidine,
[2-(hexahydro-1(2H)-azocinyl)ethyl]-, sulfate (1:1). Guanethidine
has been marketed under the trade name Ismelin.
Other agents have been shown to create partial or complete
sympathectomy as well. These include immunosympathectomy agent
anti-nerve growth factor (anti-NGF); auto-immune sympathectomy
agents anti-dopamine beta-hydroxylase (anti-D.beta.H) and
anti-acetylcholinesterase (anti-AChe); chemical sympathectomy
agents 6-hydroxyldopamine (6-OHDA), bretylium tosylate, guanacline,
and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4); and
immunotoxin sympathectomy agents OX7-SAP, 192-SAP, anti-dopamine
beta-hydroxylase saporin (DBH-SAP), and anti-dopamine
beta-hydroxylase immunotoxin (DHIT). A full description of these
agents is found in Picklo M J, J Autonom Nery Sys 1997; 62:111-125.
Phenol and ethanol have also been used to produce chemical
sympathectomy and are also useful in the methods of this invention.
Other sympatholytic agents include alpha-2-agonists such as
clonidine, guanfacine, methyldopa, guanidine derivatives like
betanidine, guanethidine, guanoxan, debrisoquine, guanoclor,
guanazodine, guanoxabenz, guancydine, guanadrel and the like;
imadazoline receptor agonists such as moxonidine, relmenidine and
the like; ganglion-blocking or nicotinic antagonists such as
mecamylamine, trimethaphan and the like; MAOI inhibitors such as
pargyline and the like; adrenergic uptake inhibitors such as
rescinnamine, reserpine and the like; tyrosine hydroxylase
inhibitors such as metirosine and the like; alpha-1 blockers such
as prazosin, indoramin, trimazosin, doxazosin, urapidil and the
like; non-selective alpha blockers such as phentolamine and the
like; serotonin antagonists such as ketanserin and the like; and
endothelin antagonists such as bosentan, ambrisentan, sitaxentan,
and the like.
Renal sympathetic nerve activity leads to the production of
norepinephrine. It has been well established that renal
sympathectomy (also known as renal artery sympathectomy or renal
denervation) reduces norepinephrine buildup in the kidney. This has
been measured by studies that involved surgical denervation of the
renal artery, published by Connors in 2004 for pigs, Mizelle in
1987 for dogs, and Katholi in 1981 for rats. In fact, it has been
shown that surgical denervation of one renal artery with sham
surgery on the contralateral renal artery results in reductions of
approximately 90% or more in kidney norepinephrine content on the
denervated side compared to the control side. This evidence of
denervation is therefore used as a surrogate to test denervation
methods in large animals like pigs, since these animals do not
develop essential hypertension normally. Further evidence of the
link between denervation and norepinephrine buildup has been
presented in norepinephrine spillover from the kidney, measured in
the renal vein outflow blood [as reported by Krum et al, Lancet
2009]. Further linkage has been made between the ability to reduce
renal norepinephrine in large animal models (such as porcine
models) indicating the ability to reduce blood pressure in
hypertensive human patients.
Complete sympathectomy of the renal arteries remains problematic
due to the side effects inherent with reducing blood pressure below
normal levels. Over the past 30 years, an ongoing debate has taken
place around the presence and impact of a "J-curve" when relating
the reduction of hypertension to therapeutic benefit [Cruickshank
J, Current Cardiology Reports 2003; 5:441-452]. This debate has
highlighted an important point in the treatment of hypertension:
that while reduction in blood pressure may reduce cardiovascular
morbidity and mortality rates, too great a reduction leads to a
reversal in benefit. With surgical sympathectomy, the renal
efferent and afferent nerves are completely removed, so there is no
ability to "titrate" the amount of sympathectomy for a given
patient. An improved method is proposed here for a therapy that can
be titrated to the needs of the individual patient with adventitial
delivery of sympatholytic agents capable of creating dose-dependent
sympathectomy. Given appropriate dose titration, therapy can be
tailored to reach the bottom of the J-curve without overshooting
and leading to hypotensive effects.
For all of these reasons, it would be desirable to provide
additional and improved methods and kits for the
adventitial/perivascular delivery of sympatholytic or sympathetic
nerve blocking agents (together with other agents that can modulate
nerve function, neuromodulating agents) to accomplish biological
and reversible denervation while not creating injury to the blood
vessel or aggravating the underlying vascular disease. In
particular, it would be beneficial to provide methods which
specifically target therapeutic concentrations of the sympathetic
neuromodulating agents into the adventitia and perivascular tissue,
where the sympathetic efferent and afferent nerves are located. It
would be further beneficial if the methods could efficiently
deliver the drugs into the targeted tissue and limit or avoid the
loss of drugs into the luminal blood flow. It would be further
beneficial if the methods could enhance the localization of
sympathetic neuromodulating agents in the adventitia and
peri-adventitia, avoiding diffusion of agents to surrounding organs
or nerves. It would be still further beneficial if the persistence
of such therapeutic concentrations of the sympathetic
neuromodulating agents in the tissue were also increased,
particularly in targeted tissues around the sympathetic nerves,
including the adventitial tissue surrounding the blood vessel wall.
Additionally, it would be beneficial to increase the uniformity of
sympathetic neuromodulating agent delivery over the desired
treatment zone. Still further, it would be desirable if the tissue
region or treatment zone into which the neuromodulating agent is
delivered could be predicted and tracked with the use of visual
imaging and positive feedback to an operating physician. At least
some of these objectives will be met by the inventions described
hereinafter.
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Breen L T, Mutafova-Yambolieva V N, "Nicotinamide adenine
dinucleotide is released from sympathetic nerve terminals via a
botulinum neurotoxin A-mediated mechanism in canine mesenteric
artery", Am J Physiol Heart Circ Physiol 2006; 290:H1818-H1825.
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neurotoxin C1 cleaves both syntaxin and SNAP-25 in intact and
permeabilized chromaffin cells: correlation with its blockade of
catecholamine release", Biochemistry 1996; 35(8):2630-6. Demas G E
and Bartness T J, "Novel Method for localized, functional
sympathetic nervous system denervation of peripheral tissue using
guanethidine", Journal of Neuroscience Methods 2001; 112:21-28.
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norepinephrine in various peripheral tissues: guanethidine
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changes in the nervous structures under the chemical sympathectomy
with guanethidine", Journal of the Autonomic Nervous System 1998;
74(2-3):82-85.
The following references are pertinent to self-assembling peptide
hydrogel matrix, useful to extend pharmacokinetics as described in
this invention: Koutsopoulos S, Unsworth L D, Nagai Y, Zhang S,
"Controlled release of functional proteins through designer
self-assembling peptide nanofiber hydrogel scaffold", Proc Natl
Acad Sci 2009; 106(12):4623-8. Nagai Y, Unsworth L D, Koutsopoulos
S, Zhang S, "Slow release of molecules in self-assembling peptide
nanofiber scaffold", J Control Rel. 2006; 115:18-25. BD.TM.
PuraMatrix.TM. Peptide Hydrogel (Catalog No. 354250) Guidelines for
Use, BD Biosciences, SPC-354250-G Rev 4.0. Erickson I E, Huang A H,
Chung C, Li R T, Burdick J A, Mauck R L, Tissue Engineering Part A.
online publication ahead of print. doi:10.1089/ten.tea.2008.0099.
Henriksson H B, Svanvik T, Jonsson M, Hagman M, Horn M, Lindahl A,
Brisby H, "Transplantation of human mesenchymal stems cells into
intervertebral discs in a xenogeneic porcine model", Spine 2009
Jan. 15; 34(2):141-8. Wang S, Nagrath D, Chen P C, Berthiaume F,
Yarmush M L, "Three-dimensional primary hepatocyte culture in
synthetic self-assembling peptide hydrogel", Tissue Eng Part A 2008
February; 14(2):227-36. Thonhoff J R, Lou D I, Jordan P M, Zhao X,
Wu P, "Compatibility of human fetal neural stem cells with hydrogel
biomaterials in vitro", Brain Res 2008 Jan. 2; 1187:42-51. Spencer
N J, Cotanche D A, Klapperich C M, "Peptide- and collagen-based
hydrogel substrates for in vitro culture of chick cochleae",
Biomaterials 2008 March; 29(8):1028-42. Yoshida D, Teramoto A, "The
use of 3-D culture in peptide hydrogel for analysis of discoidin
domain receptor 1-collagen interaction", Cell Adh Migr 2007 April;
1(2):92-8. Kim M S, Yeon J H, Park J K, "A microfluidic platform
for 3-dimensional cell culture and cell-based assays", Biomed
Microdevices 2007 February; 9(1):25-34. Misawa H, Kobayashi N,
Soto-Gutierrez A, Chen Y, Yoshida A, Rivas-Carrillo J D,
Navarro-Alvarez N, Tanaka K, Miki A, Takei J, Ueda T, Tanaka M,
Endo H, Tanaka N, Ozaki T, "PuraMatrix facilitates bone
regeneration in bone defects of calvaria in mice", Cell Transplant
2006; 15(10):903-10. Yamaoka H, Asato H, Ogasawara T, Nishizawa S,
Takahashi T, Nakatsuka T, Koshima I, Nakamura K, Kawaguchi H, Chung
U I, Takato T, Hoshi K, "Cartilage tissue engineering using human
auricular chondrocytes embedded in different hydrogel materials", J
Biomed Mater Res A 2006 July; 78(1):1-11. Bokhari M A, Akay G,
Zhang S, Birch M A, "The enhancement of osteoblast growth and
differentiation in vitro on a peptide hydrogel-polyHIPE polymer
hybrid material", Biomaterials 2005 September; 26(25):5198-208.
Zhang S, Semino C, Ellis-Behnke R, Zhao X, Spirio L, "PuraMatrix:
Self-assembling Peptide Nanofiber Scaffolds. Scaffolding in Tissue
Engineering", CRC Press, 2005. Davis M E, Motion J P, Narmoneva D
A, Takahashi T, Hakuno D, Kamm R D, Zhang S, Lee R T, "Injectable
self-assembling peptide nanofibers create intramyocardial
microenvironments for endothelial cells", Circulation 111: 442-450,
2005.
The following references are pertinent to carotid sinus syndrome
(CSS) and adventitial denervation as a treatment option: Healey J,
Connolly S J, Morillo C A, "The management of patients with carotid
sinus syndrome: is pacing the answer", Clin Auton Res 2004 October;
14 Suppl 1:80-6. Toorop R J, Schelting a M R, Bender M H, Charbon J
A, Huige M C, "Effective surgical treatment of the carotid sinus
syndrome", J Cardiovasc Surg (Torino) 2008 Oct. 24. Toorop R J,
Schelting a M R, Moll F L, "Adventitial Stripping for Carotid Sinus
Syndrome", Ann Vasc Surg 2009 Jan. 7.
BRIEF SUMMARY OF THE INVENTION
Methods and kits according to the present invention are able to
achieve enhanced concentrations of guanethidine agents in targeted
tissues surrounding a blood vessel, particularly adventitial
tissues, more particularly renal artery and vein adventitial
tissues which surround the renal sympathetic nerves. The methods
rely on vascular adventitial delivery of the guanethidine using a
catheter having a deployable needle. The catheter is advanced
intravascularly to a target injection site (which may or may not be
within a renal artery) in a blood vessel. The needle is advanced
through the blood vessel wall so that an aperture on the needle is
positioned in adventitial tissue typically within a perivascular
region (defined below) surrounding the injection site, and the
guanethidine is delivered into the perivascular region through the
microneedle.
This delivery protocol has been found to have a number of
advantages. First, direct injection into the perivascular region
has been found to immediately provide relatively high
concentrations of the guanethidine in the adventitial tissue
immediately surrounding the injected tissue. Second, following
injection, it has been found that the injected guanethidine will
distribute circumferentially to substantially uniformly surround
the blood vessel at the injection site as well as longitudinally to
reach positions which are 1 cm, 2 cm, 5 cm, or more away from the
injection site, depending upon the liquid formulation in which the
drug is carried. In addition, injected guanethidine may be found to
distribute transmurally throughout the endothelial and intimal
layers of the blood vessel, as well as in the media, or muscular
layer, of the blood vessel wall. Pathways for the distribution of
the guanethidine are presently believed to exist through the fatty
connective tissue forming the adventitia and perivascular space and
may also exist in the vasa vasorum and other capillary channels
through the connective tissues. Third, the delivered and
distributed guanethidine will persist for hours or days, again
depending on the carrier, lipophilicity, and potential to bind to
cell surface receptors and undergo endocytosis. Thus, a prolonged
therapeutic effect based on the guanethidine may be achieved in
both the adventitia and the blood vessel wall. Fourth, after the
distribution has occurred, the concentration of the guanethidine
throughout its distribution region will be highly uniform. While
the concentration of the guanethidine at the injection site will
always remain the highest, concentrations at other locations in the
peripheral adventitia around the injection site will usually reach
at least about 10% of the concentration at the injection site,
often being at least about 25%, and sometimes being at least about
50%. Similarly, concentrations in the adventitia at locations
longitudinally separated from the injection site by about 5 cm will
usually reach at least 5% of the concentration at the injection
site, often being at least 10%, and sometimes being at least 25%.
Fifth, the distribution can be traced with the use of
radio-contrast agents by X-ray (or by hyperechoic or hypoechoic
contrast agents by ultrasound or MRI contrast agents by magnetic
resonance) in order to determine the extent of diffusion, allowing
one to limit the injection based on reaching a desirable diffusion
region, increase the injection based on the desire to reach a
greater diffusion region, or change the injection site based on an
inadequate diffusion range based on the location of the needle tip,
which may be embedded in a thick plaque or located intraluminally
from a thick calcification. Finally, the distributed guanethidine
accumulates selectively within sympathetic neurons via the amine
uptake pump, and can accumulate within neurons in vivo to
concentrations of 0.5 to 1.0 millimolar (mM).
The adventitial tissue surrounding arteries and veins in the body
contains sympathetic nerves that provide signal pathways for the
regulation of hormones and proteins secreted by the cells and
organs of the body. The efferent (conducting away from the central
nervous system) and afferent (conducting toward the central nervous
system) sympathetic nerves that line the renal artery are held
within this adventitial connective tissue. The sympathetic nervous
system is responsible for up- and down-regulation of chemicals in
the body that lead to homeostasis. In the case of hypertension, the
sympathetic nerves that run from the spinal cord to the kidneys
signal the body to produce norepinephrine at superphysiological
levels, which leads to a cascade of signals causing a rise in blood
pressure. Denervation of the renal arteries (and to some extent the
renal veins) removes this response and allows a return to normal
blood pressure.
The benefits of the present invention are achieved by delivering
the guanethidine optionally with other agents that can modulate the
transmission of nerve signals into the adventitia or perivascular
region surrounding a renal artery or vein. The perivascular region
is defined as the region beyond the external elastic lamina of an
artery or beyond the tunica media of a vein. Usually, injection
will be made directly into the region of the adventitia comprised
primarily of adventitial fat cells but also comprised of
fibroblasts, vasa vasorum, lymphatic channels, and nerve cells, and
it has been found that the neuromodulating agents disperse through
the adventitia circumferentially, longitudinally, and transmurally
from injection site. Such distribution can provide for delivery of
therapeutically effective concentrations of the neuromodulating
drugs directly to the area where nerve cells can be affected. This
is difficult or impossible to accomplish with other delivery
techniques (such as parenteral hypodermic needle injection).
The adventitia is a layer of fatty tissue surrounding the arteries
of the human and other vertebrate cardiovascular systems. The
external elastic lamina (EEL) separates the fatty adventitial
tissue from muscular tissue that forms the media of the arterial
wall. Needles of the present invention pass through the muscular
tissue of the blood vessel and the EEL in order to reach the
adventitia and perivascular space into which the drug is injected.
The renal arteries or veins that are subject of this invention
usually have an internal (lumen) diameter of between 1 mm and 10
mm, more often between 3 and 6 mm, particularly after angioplasty
has been used to compress any plaque that may have been impinging
on the lumen. The thickness of the intima and media, which separate
the lumen from the EEL, are usually in the range from 200 .mu.m to
3 mm, more often in the range from 500 .mu.m to 1 mm. The
adventitial tissue surrounding the EEL may be several millimeters
thick, but the sympathetic nerves that run to the kidneys are
usually within 3 mm outside the EEL, more often within 1 mm outside
the EEL.
The guanethidine agents injected in accordance with the methods
described in this invention will typically either be in fluid form
themselves, or will be suspended in aqueous or fluid carriers in
order to permit dispersion of the neuromodulating agents through
the adventitia. Drugs may also be suspended in self-assembling
hydrogel carriers in order to contain the diffusion and extend the
retention of agents in the area of tissue local to the injection
site.
The delivery of guanethidine agents into the adventitia outside the
EEL leads to the direct targeting and interruption of the
sympathetic nerve signaling pathway. Sympathectomy may be
accomplished with immunosympathectomy agents such as anti-nerve
growth factor (anti-NGF); auto-immune sympathectomy agents such as
anti-dopamine beta-hydroxylase (anti-D.beta.H) and
anti-acetylcholineesterase (anti-AChe); chemical sympathectomy
agents such as 6-hydroxydpoamine (6-OHDA), phenol, ethanol,
bretylium tosylate, guanethidine, guanacline, and
N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4); immunotoxin
sympathectomy agents such as OX7-SAP, 192-SAP, anti-dopamine
beta-hydroxylase saporin (DBH-SAP), and anti-dopamine
beta-hydroxylase immunotoxin (DHIT); or combinations thereof. Other
sympatholytic agents include alpha-2-agonists such as clonidine,
guanfacine, methyldopa, guanidine derivatives like betanidine,
guanethidine, guanoxan, debrisoquine, guanoclor, guanazodine,
guanoxabenz, guancydine, guanadrel and the like; imadazoline
receptor agonists such as moxonidine, relmenidine and the like;
ganglion-blocking or nicotinic antagonists such as mecamylamine,
trimethaphan and the like; MAOI inhibitors such as pargyline and
the like; adrenergic uptake inhibitors such as rescinnamine,
reserpine and the like; tyrosine hydroxylase inhibitors such as
metirosine and the like; alpha-1 blockers such as prazosin,
indoramin, trimazosin, doxazosin, urapidil and the like;
non-selective alpha blockers such as phentolamine and the like;
serotonin antagonists such as ketanserin and the like; and
endothelin antagonists such as bosentan, ambrisentan, sitaxentan,
and the like.
Systemic administration of chronic, high doses of guanethidine can
cause functional sympathectomy, but at the expense of terrible side
effects. Guanethidine causes sympathectomy by preventing the
release of norepinephrine from sympathetic nerve terminals by
interfering with the excitatory release of vesicles carrying
norepinephrine, by replacing norepinephrine in the synaptic
vesicles, by inhibiting oxidative phosphorylation in mitochondria
with an effective dose in 50% of cells (ED.sub.50) of 0.5 to 0.9
mM, by inhibiting retrograde transport of trophic factors such as
nerve growth factor, and also by exerting cytotoxic effects by an
immune-mediated mechanism.
In a first aspect of the present invention, a method for
distributing guanethidine or a combination of guanethidine with
other agents into the adventitial tissue and nerves surrounding a
living vertebrate host's renal artery, such as a human renal
artery, comprises positioning a needle through the wall of a renal
blood vessel and delivering an amount of the neuromodulating agent
or combination of agents therethrough. In specific methods, the
guanethidine may be injected or otherwise delivered into the
adventitia surrounding both of the patient's renal arteries.
Alternatively, or additionally, the guanethidine may also be
injected or otherwise delivered into either or both of the
patient's renal veins.
The needle is inserted, preferably in a substantially normal
direction, into the wall of a vessel (artery or vein) to eliminate
as much trauma to the patient as possible. Until the microneedle is
at the site of an injection, it is positioned out of the way so
that it does not scrape against arterial or venous walls with its
tip. Specifically, the microneedle remains enclosed in the walls of
an actuator or sheath attached to a catheter so that it will not
injure the patient during intervention or the physician during
handling. When the injection site is reached, movement of the
actuator along the vessel terminated, and the actuator is operated
to cause the microneedle to be thrust outwardly, substantially
perpendicular to the central axis of a vessel, for instance, in
which the catheter has been inserted.
The aperture of the microneedle will be positioned so that it lies
beyond the external elastic lamina (EEL) of the blood vessel wall
and into the perivascular region surrounding the wall. Usually, the
aperture will be positioned at a distance from the inner wall of
the blood vessel which is equal to at least 10% of the mean luminal
diameter of the blood vessel at the injection site. Preferably, the
distance will be in the range from 10% to 75% of the mean luminal
diameter.
When the aperture of the microneedle is located in the tissue
outside of the EEL surrounding the blood vessel, the guanethidine
is delivered through the needle aperture, at which point the agent
or combination distributes substantially completely
circumferentially through adventitial tissue surrounding the blood
vessel at the site of the microneedle. Usually, the guanethidine
will further distribute longitudinally along the blood vessel over
a distance of at least 1 to 2 cm, and can extend to greater
distances depending on dosage (volume) injected, within a time
period no greater than 60 minutes, often within 5 minutes or less.
While the concentration of the guanethidine in the adventitia will
decrease in the longitudinal direction somewhat; usually, the
concentration measured at a distance of 2 cm from the injection
site will usually be at least 5% of the concentration measured at
the same time at the injection site, often being at least 10%,
frequently being as much as 25%, and sometimes being as much as
50%. The concentration profile is greatly dependent on the size of
the molecule or particle delivered into the adventitial and
perivascular tissue. The concentration profile can be further
tailored by the use of different carriers and excipients within the
liquid or gel formulation in which the agent is carried.
The location of the aperture may be detected in advance of placing
the full dose of guanethidine into the adventitia by the use of,
for example, X-ray, ultrasonic, or magnetic resonance imaging of a
radio-contrast agent. The contrast agent may be delivered at the
same time as the therapeutic agent, either in or out of solution
with the therapeutic agent, or it may be delivered prior to the
therapeutic agent to detect and confirm that the needle aperture is
in the desirable tissue location outside the EEL. After determining
the successful placement of the needle aperture, continued
injection can be made through the needle under image guidance. Such
methods for delivering agents provide the physician a positive
visual feedback as to the location of the injection and diffusion
range, and also to titrate the dose based on diffusion range and
physiological response. The amounts of the agents delivered into
the perivascular region may vary considerably, but imaging agents
delivered before the therapeutic agent will usually be in the range
of 10 to 200 .mu.l, and often will be in the range of 50 to 100
.mu.l. Therapeutic agent injection will then typically be in the
range from 10 .mu.l to 10 ml, more usually being from 100 .mu.l to
5 ml, and often being from 500 .mu.l to 3 ml.
Specific methods for treatment of hypertension comprise positioning
a microneedle through the wall of a renal artery or vein and
delivering an effective dose of guanethidine to the adventitia and
perivascular tissues surrounding such vessels leading from the
aorta to the kidney or from the kidney to the vena cava. A
therapeutic effective dose of guanethidine to create sympathectomy
and reduce norepinephrine release, thereby reducing blood pressure
can be monitored by the operating physician and titrated based on
patient characteristics. This dose around each renal artery may be
in the range from 10 .mu.g to 200 mg, usually 50 .mu.g to 100 mg,
more usually being from 100 .mu.g to 50 mg, and even more usually
being from 500 .mu.g to 30 mg, and sometimes being from 500 .mu.g
to 10 mg. Optionally, the activity of the guanethidine in target
tissues comprises the use of agents that are endocytosed by nerve
cells and then remain in the cells for long periods of time before
becoming inactive.
The activity of the guanethidine may also be extended in target
tissues by the delivery of the guanethidine within a hydrogel that
has a capacity for self assembly, such as a self-assembling peptide
hydrogel matrix. When co-administered with the hydrogel material,
molecules of the active agent are trapped in a nanofiber matrix as
the hydrogel self-assembles due to contact with physiologic
conditions. The hydrogel matrix may have fibers with diameter from
1 to 100 nm, for example, and pores with diameter from 1 to 300 nm,
for example. Molecules trapped within the matrix may slowly diffuse
through the porous structure or remain trapped within pores. The
matrix may be slowly resorbed by the surrounding tissue, as peptide
matrices are commonly known to do, and become simple amino acids.
As the matrix is resorbed, trapped molecules of the active agent
are then released into the surrounding tissues, leading to an
ability to extend the pharmacokinetics of the neuromodulating
agents.
An exemplary hydrogel for use with the methods described in this
invention is a self-assembling peptide hydrogel that comprises
alternating hydrophilic and hydrophobic amino acids which, in the
presence of physiological conditions, will spontaneously
self-organize into an interwoven nanofiber matrix with fiber
diameters of 10-20 nm. In the presence of proteins and small
molecules, the nanofiber matrix traps the bioactive molecules
within pores ranging from 5 to 200 nm. This self-assembling
peptide, acetyl-(Arg-Ala-Asp-Ala).sub.4-CONH.sub.2
[Ac-(RADA).sub.4-CONH.sub.2] (PuraMatrix.TM.), has been reported as
an efficient slow-delivery carrier of small molecules. The release
of proteins from the nanofiber matrix has been shown to include at
least two phases. The first is a "burst" of released material,
wherein it has been theorized that the protein material that is
loosely trapped within large pores diffuses out rapidly (over a
period of several hours), then a slower release of more tightly
trapped material occurs over at least several days and is governed
by Brownian motion of the proteins moving through the tight matrix.
A third aspect to the release kinetics is the breakdown of the
peptide matrix at its boundary, thus a release of trapped protein
as the peptide is resorbed by surrounding tissue. One of the
advantages of the peptide hydrogel as compared to "traditional"
hydrogels is that the breakdown of the peptide structure results
only in amino acid byproducts, which are easily metabolized by the
body. PuraMatrix is available from BD Bioscience as BD.TM.
PuraMatrix.TM. Peptide Hydrogel for research use only in 1%
concentration. It is used primarily as a cell culture agent, but
with application for in vivo use in the delivery of cells and
bioactive agents. PuraMatrix has been studied for its uses as a
matrix for engineering cartilage using mesenchymal cells and
chondrocytes, as a carrier of mesenchymal cells for spinal disc
injury, as a hepatocyte culture matrix, to support differentiation
of human fetal neural stem cells in vitro, and other cell culture
and regenerative medical applications. Biocompatibility studies of
Puramatrix have shown that it integrates well with tissue, much
like other extracellular matrix structures, and can be resorbed
over a period of several weeks. It has also been shown that
functional vascular structures can be seen in the nanofiber
microenvironments by 28 days after injection. With specific
relevance to this invention, PuraMatrix has also been shown to have
no deleterious effect on the proteins that it entraps or elutes
over time.
In yet another aspect of the present invention, methods to treat
other diseases resulting from hyperactivity of sympathetic and
parasympathetic nerves comprise delivery of guanethidine for the
chemical or neuromodulating denervation of arteries. While this
therapy may most often be applied to renal arteries, other vascular
beds can benefit from these methods. For example, denervation of
the carotid artery can be used to treat patients with carotid sinus
syndrome (CSS), a condition that leads to dizziness and syncope,
but can be rectified by carotid adventitial denervation.
In yet another aspect of the present invention, a method for
treating vascular disease comprises the delivery of guanethidine to
the adventitia around blood vessels. The development of
atherosclerosis, vulnerable plaques, and the growth of hyperplastic
neointima have each been shown to rely on parasympathetic and
sympathetic nerve signaling pathways. When interrupted, these
signal pathways no longer produce the agents that end up causing
the vascular inflammation that results in mortality and morbidity
from associated ischemic complications.
One particular advantage of this invention is the ability to
reverse the therapy in the case that a patient responds poorly to
renal denervation. For example, if toxins are used to reduce
neurotransmission, anti-toxins can be delivered (either
systemically or locally) to reverse the effect and improve the
patient's health. Other methods for renal sympathetic denervation
have relied on surgical cutting of nerves or radiofrequency energy
transmission to nerves to cause damage beyond which the nerves
cannot transmit signals. Each of these previous methods is
irreversible (though the RF energy transmission can lead to
non-permanent effects that may wear off after months to years). If
patients respond poorly to either the surgical or RF denervation
procedures, there is therefore little recourse.
Another particular advantage of this invention is that side effects
are limited by the very low doses that lead to therapeutic effect,
often less than 50 mg of guanethidine (whereas systemic doses of
5-50 mg/kg/day do not produce reliable sympathectomy in humans),
because the methods described in this invention allow precise
targeting of guanethidine into the tissue in which the sympathetic
nerves are located.
Another particular advantage of this invention is that the
guanethidine delivered into the adventitia according to the methods
described above does not lead to death of smooth muscle cells,
inflammation, or restenosis, all of which can result from
radiofrequency energy transmission into arterial walls from an
endoluminal aspect. Rather, the agents directly target the
sympathetic and parasympathetic nerves that run through the
adventitia, leaving the smooth muscle and endothelium of the vessel
in a functional state, healthy and able to respond to physiological
signals coming from the blood or lymph traveling around and through
the vessel.
Another particular advantage of this invention is that the
guanethidine can be tracked during delivery by the use of contrast
agents. This allows physicians to ensure that large enough doses
are given to fully treat the adventitia, but small enough doses are
used such that the diffusion is limited to the area of anatomical
interest This limits the potential for guanethidine to reach the
central nervous system. The use of imaging agents in coordination
with blood pressure monitoring allows physicians to actively
monitor the effect of the dose while controlling the treatment
range so as not to influence surrounding tissues or nervous
systems.
In still further aspects of the present invention, kits for
delivering guanethidine to a patient suffering from hypertension
comprise a catheter, instructions for use of the catheter, and
instructions for delivery of the agent. The catheter has a
microneedle which can be advanced from a blood vessel lumen through
a wall of the blood vessel to position an aperture of the
microneedle at a perivascular space surrounding the blood vessel.
The instructions for use set forth any of the exemplary treatment
protocols described above. The kit may also include one or more
stents and one or more angioplasty balloons that can be used to
open the renal arteries and improve blood flow to the kidneys.
In a further aspect of the present invention, kits for delivering
guanethidine agents to the vascular adventitia of patients
suffering from disease comprise a catheter, guanethidine which may
or may not be in formulation with a carrier that can extend the
elution kinetics of the agent into adventitial and adjacent
tissues, instructions for use of the catheter, and dosage
guidelines for the agent. The catheter has a microneedle which can
be advanced from a blood vessel lumen through the wall of the blood
vessel to position an aperture of the microneedle at a location
outside the EEL of the blood vessel in the perivascular tissue or
adventitia. The guanethidine will usually be able to distribute
circumferentially and longitudinally in the perivascular space and
adventitia surrounding the blood vessel over a distance of at least
1 cm within a time of no greater than 5 minutes, usually within 1
minute or less. The instructions for use set forth any of the
exemplary treatment protocols described above. The kit may also
include one or more stents and one or more angioplasty balloons
that can be used to open the renal arteries and improve blood flow
to the kidneys.
The present invention provides methods that are enhanced by
catheters that place a needle aperture outside the EEL of a blood
vessel by deploying the needle from the inside of the vessel. These
catheters may take on various forms. In one exemplary embodiment, a
balloon or inflatable actuator is inflated to unfurl a balloon from
around a microneedle that his inserted roughly perpendicularly
through the vessel wall, as further described in commonly owned
U.S. Pat. Nos. 6,547,803; 7,547,294; and 7,666,163. Another such
exemplary embodiment employs a balloon that inflates and translates
a needle and extrudes the needle tip along a path into the vessel
wall. Such an exemplary embodiment has been shown with commonly
owned U.S. Pat. No. 7,141,041. In each of these exemplary
embodiments, multiple components may be combined into the same
balloon or pressure component, such that one part of the wall is
non-distensible and another part of the wall is compliant or
elastomeric, such that a single inflation step, whether it involves
volume or pressure, may be useful to activate both the
non-distensible and compliant structures simultaneously or in
series. Such enhanced embodiments for delivery catheters are
described in U.S. Pat. No. 7,691,080. Exemplary methods which can
be used for delivering neuromodulating agents into the adventitia
are described in copending commonly owned application Ser. No.
10/691,119. The full disclosure of each of these commonly owned
patents and applications are incorporated herein by reference.
It is recognized that the use of these devices and techniques to
deliver to the adventitia around renal arteries is useful in the
treatment of hypertension, it is also evident that the use of these
devices and techniques can be applied to other arteries, such as
the carotid artery, to accomplish similar goals.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A is a schematic, perspective view of an intraluminal
injection catheter suitable for use in the methods and systems of
the present invention.
FIG. 1B is a cross-sectional view along line 1B-1B of FIG. 1A.
FIG. 1C is a cross-sectional view along line 1C-1C of FIG. 1A.
FIG. 2A is a schematic, perspective view of the catheter of FIGS.
1A-1C shown with the injection needle deployed.
FIG. 2B is a cross-sectional view along line 2B-2B of FIG. 2A.
FIG. 3 is a schematic, perspective view of the intraluminal
catheter of FIGS. 1A-1C injecting therapeutic agents into an
adventitial space surrounding a body lumen in accordance with the
methods of the present invention.
FIGS. 4A-4D are cross-sectional views of the inflation process of
an intraluminal injection catheter useful in the methods of the
present invention.
FIGS. 5A-5C are cross-sectional views of the inflated intraluminal
injection catheter useful in the methods of the present invention,
illustrating the ability to treat multiple lumen diameters.
FIG. 6 is a perspective view of a needle injection catheter useful
in the methods and systems of the present invention.
FIG. 7 is a cross-sectional view of the catheter FIG. 6 shown with
the injection needle in a retracted configuration.
FIG. 8 is a cross-sectional view similar to FIG. 7, shown with the
injection needle laterally advanced into luminal tissue for the
delivery of therapeutic or diagnostic agents according to the
present invention.
FIG. 9 is a schematic illustration of an artery together with
surrounding tissue illustrating the relationship between the
perivascular tissue, the adventitia, and the blood vessel wall
components.
FIG. 10A is a schematic illustration of the kidney and arterial
structure that brings blood to the kidney.
FIG. 10B is a schematic illustration of FIG. 10A with sympathetic
nerves shown leading from the aorta around the renal artery to the
kidney.
FIG. 10C is a cross-sectional view along line 10C-10C of FIG.
10B.
FIGS. 11A-11C are cross-sectional views similar to FIGS. 4A and 4D,
shown with the injection needle advanced into the adventitia for
progressive delivery of agents to sympathetic nerves according to
the present invention.
FIG. 11D is a cross-sectional view along line 11D-11D of FIG.
11A.
FIG. 11E is a cross-sectional view along line 11E-11E of FIG.
11B.
FIG. 11F is a cross-sectional view along line 11F-11F of FIG.
11C.
FIG. 12 is a graphical presentation of experimental data described
herein.
DETAILED DESCRIPTION OF THE INVENTION
The present invention will preferably utilize microfabricated
catheters for intravascular injection. The following description
and FIGS. 1-8 provide three representative embodiments of catheters
having microneedles suitable for the delivery of a neuromodulating
agent into a perivascular space or adventitial tissue. A more
complete description of the catheters and methods for their
fabrication is provided in U.S. Pat. Nos. 7,141,041; 6,547,803;
7,547,294; 7,666,163 and 7,691,080, the full disclosures of which
have been incorporated herein by reference.
The present invention describes methods and kits useful for the
delivery of neuromodulating agents into the adventitia around renal
arteries in order to reduce blood pressure in the treatment of
hypertension. In each kit, a delivery catheter may be combined with
instructions for use and a therapeutically effective amount of a
neuromodulating agent as defined above.
As shown in FIGS. 1A-2B, a microfabricated intraluminal catheter 10
includes an actuator 12 having an actuator body 12a and central
longitudinal axis 12b. The actuator body more or less forms a
U-shaped or C-shaped outline having an opening or slit 12d
extending substantially along its length. A microneedle 14 is
located within the actuator body, as discussed in more detail
below, when the actuator is in its unactuated condition (furled
state) (FIG. 1B). The microneedle is moved outside the actuator
body when the actuator is operated to be in its actuated condition
(unfurled state) (FIG. 2B).
The actuator may be capped at its proximal end 12e and distal end
12f by a lead end 16 and a tip end 18, respectively, of a
therapeutic catheter 20. The catheter tip end serves as a means of
locating the actuator inside a body lumen by use of a radio opaque
coatings or markers. The catheter tip also forms a seal at the
distal end 12f of the actuator. The lead end of the catheter
provides the necessary interconnects (fluidic, mechanical,
electrical or optical) at the proximal end 12e of the actuator.
Retaining rings 22a and 22b are located at the distal and proximal
ends, respectively, of the actuator. The catheter tip is joined to
the retaining ring 22a, while the catheter lead is joined to
retaining ring 22b. The retaining rings are made of a thin, on the
order of 10 to 100 microns (.mu.m), substantially flexible but
relatively non-distensible material, such as Parylene (types C, D
or N), or a metal, for example, aluminum, stainless steel, gold,
titanium or tungsten. The retaining rings form a flexible but
relatively non-distensible substantially "U"-shaped or "C"-shaped
structure at each end of the actuator. The catheter may be joined
to the retaining rings by, for example, a butt-weld, an ultra sonic
weld, integral polymer encapsulation or an adhesive such as an
epoxy or cyanoacrylate.
The actuator body further comprises a central, expandable section
24 located between retaining rings 22a and 22b. The expandable
section 24 includes an interior open area 26 for rapid expansion
when an activating fluid is supplied to that area. The central
section 24 is made of a thin, semi-flexible but relatively
non-distensible or flexible but relatively non-distensible,
expandable material, such as a polymer, for instance, Parylene
(types C, D or N), silicone, polyurethane or polyimide. The central
section 24, upon actuation, is expandable somewhat like a
balloon-device.
The central section is capable of withstanding pressures of up to
about 200 psi upon application of the activating fluid to the open
area 26. The material from which the central section is made of is
flexible but relatively non-distensible or semi-flexible but
relatively non-distensible in that the central section returns
substantially to its original configuration and orientation (the
unactuated condition) when the activating fluid is removed from the
open area 26. Thus, in this sense, the central section is very much
unlike a balloon which has no inherently stable structure.
The open area 26 of the actuator is connected to a delivery
conduit, tube or fluid pathway 28 that extends from the catheter's
lead end to the actuator's proximal end. The activating fluid is
supplied to the open area via the delivery tube. The delivery tube
may be constructed of Teflon.COPYRGT. or other inert plastics. The
activating fluid may be a saline solution or a radio-opaque
dye.
The microneedle 14 may be located approximately in the middle of
the central section 24. However, as discussed below, this is not
necessary, especially when multiple microneedles are used. The
microneedle is affixed to an exterior surface 24a of the central
section. The microneedle is affixed to the surface 24a by an
adhesive, such as cyanoacrylate. Alternatively, the microneedle
maybe joined to the surface 24a by a metallic or polymer mesh-like
structure 30 (See FIG. 2A), which is itself affixed to the surface
24a by an adhesive. The mesh-like structure may be-made of, for
instance, steel or nylon.
The microneedle includes a sharp tip 14a and a shaft 14b. The
microneedle tip can provide an insertion edge or point. The shaft
14b can be hollow and the tip can have an outlet port 14c,
permitting the injection of a neuromodulating or drug into a
patient. The microneedle, however, does not need to be hollow, as
it may be configured like a neural probe to accomplish other tasks.
As shown, the microneedle extends approximately perpendicularly
from surface 24a. Thus, as described, the microneedle will move
substantially perpendicularly to an axis of a lumen into which has
been inserted, to allow direct puncture or breach of body lumen
walls.
The microneedle further includes a neuromodulating or drug supply
conduit, tube or fluid pathway 14d which places the microneedle in
fluid communication with the appropriate fluid interconnect at the
catheter lead end. This supply tube may be formed integrally with
the shaft 14b, or it may be formed as a separate piece that is
later joined to the shaft by, for example, an adhesive such as an
epoxy. The microneedle 14 may be bonded to the supply tube with,
for example, an adhesive such as cyanoacrylate.
The needle 14 may be a 30-gauge, or smaller, steel needle.
Alternatively, the microneedle may be microfabricated from
polymers, other metals, metal alloys or semiconductor materials.
The needle, for example, may be made of Parylene, silicon or glass.
Microneedles and methods of fabrication are described in U.S.
application Ser. No. 09/877,653, filed Jun. 8, 2001, entitled
"Microfabricated Surgical Device", the entire disclosure of which
is incorporated herein by reference.
The catheter 20, in use, is inserted through an opening in the body
(e.g. for bronchial or sinus treatment) or through a percutaneous
puncture site (e.g. for artery or venous treatment) and moved
within a patient's body passageways 32, until a specific, targeted
region 34 is reached (see FIG. 3). The targeted region 34 may be
the site of tissue damage or more usually will be adjacent the
sites typically being within 100 mm or less to allow migration of
the therapeutic or diagnostic agent. As is well known in
catheter-based interventional procedures, the catheter 20 may
follow a guide wire 36 that has previously been inserted into the
patient. Optionally, the catheter 20 may also follow the path of a
previously-inserted guide catheter (not shown) that encompasses the
guide wire.
During maneuvering of the catheter 20, well-known methods of x-ray
fluoroscopy or magnetic resonance imaging (MRI) can be used to
image the catheter and assist in positioning the actuator 12 and
the microneedle 14 at the target region. As the catheter is guided
inside the patient's body, the microneedle remains furled or held
inside the actuator body so that no trauma is caused to the body
lumen walls.
After being positioned at the target region 34, movement of the
catheter is terminated and the activating fluid is supplied to the
open area 26 of the actuator, causing the expandable section 24 to
rapidly unfurl, moving the microneedle 14 in a substantially
perpendicular direction, relative to the longitudinal central axis
12b of the actuator body 12a, to puncture a body lumen wall 32a. It
may take only between approximately 100 milliseconds and five
seconds for the microneedle to move from its furled state to its
unfurled state.
The microneedle aperture, may be designed to enter body lumen
tissue 32b as well as the adventitia, media, or intima surrounding
body lumens. Additionally, since the actuator is "parked" or
stopped prior to actuation, more precise placement and control over
penetration of the body lumen wall are obtained.
After actuation of the microneedle and delivery of the agents to
the target region via the microneedle, the activating fluid is
exhausted from the open area 26 of the actuator, causing the
expandable section 24 to return to its original, furled state. This
also causes the microneedle to be withdrawn from the body lumen
wall. The microneedle, being withdrawn, is once again sheathed by
the actuator.
Various microfabricated devices can be integrated into the needle,
actuator and catheter for metering flows, capturing samples of
biological tissue, and measuring pH. The device 10, for instance,
could include electrical sensors for measuring the flow through the
microneedle as well as the pH of the neuromodulating being
deployed. The device 10 could also include an intravascular
ultrasonic sensor (IVUS) for locating vessel walls, and fiber
optics, as is well known in the art, for viewing the target region.
For such complete systems, high integrity electrical, mechanical
and fluid connections are provided to transfer power, energy, and
neuromodulatings or biological agents with reliability.
By way of example, the microneedle may have an overall length of
between about 200 and 3,000 microns (.mu.m). The interior
cross-sectional dimension of the shaft 14b and supply tube 14d may
be on the order of 20 to 250 um, while the tube's and shaft's
exterior cross-sectional dimension may be between about 100 and 500
.mu.m. The overall length of the actuator body may be between about
5 and 50 millimeters (mm), while the exterior and interior
cross-sectional dimensions of the actuator body can be between
about 0.4 and 4 mm, and 0.5 and 5 mm, respectively. The gap or slit
through which the central section of the actuator unfurls may have
a length of about 4-40 mm, and a cross-sectional dimension of about
50 .mu.m to 4 mm. The diameter of the delivery tube for the
activating fluid may be between 100 and 500 .mu.m. The catheter
size may be between 1.5 and 15 French (Fr).
Referring to FIGS. 4A-4D, an elastomeric component is integrated
into the wall of the intraluminal catheter of FIG. 1-3. In FIG.
4A-D, the progressive pressurization of such a structure is
displayed in order of increasing pressure. In FIG. 4A, the balloon
is placed within a body lumen L. The lumen wall W divides the lumen
from periluminal tissue T, or adventitia A*, depending on the
anatomy of the particular lumen. The pressure is neutral, and the
non-distensible structure forms a U-shaped involuted balloon 12
similar to that in FIG. 1 in which a needle 14 is sheathed. While a
needle is displayed in this diagram, other working elements
including cutting blades, laser or fiber optic tips, radiofrequency
transmitters, or other structures could be substituted for the
needle. For all such structures, however, the elastomeric patch 400
will usually be disposed on the opposite side of the involuted
balloon 12 from the needle 14.
Actuation of the balloon 12 occurs with positive pressurization. In
FIG. 4B, pressure (+.DELTA.P.sub.1) is added, which begins to
deform the flexible but relatively non-distensible structure,
causing the balloon involution to begin its reversal toward the
lower energy state of a round pressure vessel. At higher pressure
+.DELTA.P.sub.2 in FIG. 4C, the flexible but relatively
non-distensible balloon material has reached its rounded shape and
the elastomeric patch has begun to stretch. Finally, in FIG. 4D at
still higher pressure +.DELTA.P.sub.3, the elastomeric patch has
stretched out to accommodate the full lumen diameter, providing an
opposing force to the needle tip and sliding the needle through the
lumen wall and into the adventitia A. Typical dimensions for the
body lumens contemplated in this figure are between 0.1 mm and 50
mm, more often between 0.5 mm and 20 mm, and most often between 1
mm and 10 mm. The thickness of the tissue between the lumen and
adventitia is typically between 0.001 mm and 5 mm, more often
between 0.01 mm and 2 mm and most often between 0.05 mm and 1 mm.
The pressure +.DELTA.P useful to cause actuation of the balloon is
typically in the range from 0.1 atmospheres to 20 atmospheres, more
typically in the range from 0.5 to 20 atmospheres, and often in the
range from 1 to 10 atmospheres.
As illustrated in FIGS. 5A-5C, the dual modulus structure shown in
FIGS. 4A-4D provides for low-pressure (i.e., below pressures that
may damage body tissues) actuation of an intraluminal medical
device to place working elements such as needles in contact with or
through lumen walls. By inflation of a constant pressure, and the
elastomeric material will conform to the lumen diameter to provide
full apposition. Dual modulus balloon 12 is inflated to a pressure
+.DELTA.P.sub.3 in three different lumen diameters in FIGS. 5A, 5B,
and 5C for the progressively larger inflation of patch 400 provides
optimal apposition of the needle through the vessel wall regardless
of diameter. Thus, a variable diameter system is created in which
the same catheter may be employed in lumens throughout the body
that are within a range of diameters. This is useful because most
medical products are limited to very tight constraints (typically
within 0.5 mm) in which lumens they may be used. A system as
described in this invention may accommodate several millimeters of
variability in the luminal diameters for which they are useful.
The above catheter designs and variations thereon, are described in
published U.S. Pat. Nos. 6,547,803; 6,860,867; 7,547,294; 7,666,163
and 7,691,080, the full disclosures of which are incorporated
herein by reference. Co-pending application Ser. No. 10/691,119,
assigned to the assignee of the present application, describes the
ability of substances delivered by direct injection into the
adventitial and pericardial tissues of the heart to rapidly and
evenly distribute within the heart tissues, even to locations
remote from the site of injection. The full disclosure of that
co-pending application is also incorporated herein by reference. An
alternative needle catheter design suitable for delivering the
therapeutic or diagnostic agents of the present invention will be
described below. That particular catheter design is described and
claimed in U.S. Pat. No. 7,141,041, the full disclosure of which is
incorporated herein by reference.
Referring now to FIG. 6, a needle injection catheter 310
constructed in accordance with the principles of the present
invention comprises a catheter body 312 having a distal end 314 and
a proximal 316. Usually, a guide wire lumen 313 will be provided in
a distal nose 352 of the catheter, although over-the-wire and
embodiments which do not require guide wire placement will also be
within the scope of the present invention. A two-port hub 320 is
attached to the proximal end 316 of the catheter body 312 and
includes a first port 322 for delivery of a hydraulic fluid, e.g.,
using a syringe 324, and a second port 326 for delivering the
neuromodulating agent, e.g., using a syringe 328. A reciprocatable,
deflectable needle 330 is mounted near the distal end of the
catheter body 312 and is shown in its laterally advanced
configuration in FIG. 6.
Referring now to FIG. 7, the proximal end 314 of the catheter body
312 has a main lumen 336 which holds the needle 330, a
reciprocatable piston 338, and a hydraulic fluid delivery tube 340.
The piston 338 is mounted to slide over a rail 342 and is fixedly
attached to the needle 330. Thus, by delivering a pressurized
hydraulic fluid through a lumen 341 tube 340 into a bellows
structure 344, the piston 338 may be advanced axially toward the
distal tip in order to cause the needle to pass through a
deflection path 350 formed in a catheter nose 352.
As can be seen in FIG. 8, the catheter 310 may be positioned in a
blood vessel BV, over a guide wire GW in a conventional manner.
Distal advancement of the piston 338 causes the needle 330 to
advance into tissue T surrounding the lumen adjacent to the
catheter when it is present in the blood vessel. The therapeutic or
diagnostic agents may then be introduced through the port 326 using
syringe 328 in order to introduce a plume P of agent in the cardiac
tissue, as illustrated in FIG. 8. The plume P will be within or
adjacent to the region of tissue damage as described above.
The needle 330 may extend the entire length of the catheter body
312 or, more usually, will extend only partially into the
therapeutic or diagnostic agents delivery lumen 337 in the tube
340. A proximal end of the needle can form a sliding seal with the
lumen 337 to permit pressurized delivery of the agent through the
needle.
The needle 330 will be composed of an elastic material, typically
an elastic or super elastic metal, typically being nitinol or other
super elastic metal. Alternatively, the needle 330 could be formed
from a non-elastically deformable or malleable metal which is
shaped as it passes through a deflection path. The use of
non-elastically deformable metals, however, is less preferred since
such metals will generally not retain their straightened
configuration after they pass through the deflection path.
The bellows structure 344 may be made by depositing by parylene or
another conformal polymer layer onto a mandrel and then dissolving
the mandrel from within the polymer shell structure. Alternatively,
the bellows 344 could be made from an elastomeric material to form
a balloon structure. In a still further alternative, a spring
structure can be utilized in, on, or over the bellows in order to
drive the bellows to a closed position in the absence of
pressurized hydraulic fluid therein.
After the therapeutic material is delivered through the needle 330,
as shown in FIG. 8, the needle is retracted and the catheter either
repositioned for further agent delivery or withdrawn. In some
embodiments, the needle will be retracted simply by aspirating the
hydraulic fluid from the bellows 344. In other embodiments, needle
retraction may be assisted by a return spring, e.g., locked between
a distal face of the piston 338 and a proximal wall of the distal
tip 352 (not shown) and/or by a pull wire attached to the piston
and running through lumen 341.
The perivascular space is the potential space over the outer
surface of a "vascular wall" of either an artery or vein. Referring
to FIG. 9, a typical arterial wall is shown in cross-section where
the endothelium E is the layer of the wall which is exposed to the
blood vessel lumen L. Underlying the endothelium is the basement
membrane BM which in turn is surrounded by the intima I. The
intima, in turn, is surrounded by the internal elastic lamina IEL
over which is located the media M. In turn, the media is covered by
the external elastic lamina (EEL) which acts as the outer barrier
separating the arterial wall, shown collectively as W, from the
adventitial layer A. Usually, the perivascular space will be
considered anything lying beyond the external elastic lamina EEL,
including regions within the adventitia and beyond.
Turning now to FIG. 10A-C, the renal arterial location and
structure are shown. In FIG. 10A, the aorta (Ao) is shown as the
central artery of the body, with the right renal artery (RRA) and
left renal artery (LRA) branching from the aorta to lead blood into
the kidneys. For example, the right renal artery leads oxygenated
blood into the right kidney (RK). In FIG. 10B, the nerves (N) that
lead from the aorta to the kidney are displayed. The nerves are
shown to surround the renal artery, running roughly parallel but
along a somewhat tortuous and branching route from the aorta to the
kidney. The cross-section along line 10C-10C of FIG. 10B is then
shown in FIG. 10C. As seen in this cross-sectional representation
of a renal artery, the nerves (N) that lead from aorta to kidney
run through the arterial adventitia (A) and in close proximity but
outside the external elastic lamina (EEL). The entire arterial
cross section is shown in this FIG. 10C, with the lumen (L)
surrounded by, from inside to outside, the endothelium (E), the
intima (I), the internal elastic lamina (IEL), the media (M), the
external elastic lamina (EEL), and finally the adventitia (A).
As illustrated in FIG. 11A-F, the methods of the present invention
may be used to place an injection or infusion catheter similar to
those illustrated by FIGS. 1-5 into a vessel as illustrated in FIG.
10C and to inject a plume (P) of neuromodulating agent into the
adventitia (A) such that the agent comes in contact with the nerves
(N) that innervate the adventitia of the renal artery. As can be
seen in FIG. 11A, a catheter in the same state as FIG. 4A, wherein
an actuator is shielding a needle so that the actuator can be
navigated through the vessels of the body without scraping the
needle against the vessel walls and causing injury, is inserted
into an artery that has a media (M), an adventitia (A), and nerves
(N) within the adventitia and just outside the media. A
cross-section along line 11D-11D from FIG. 11A is shown in FIG.
11D. It can be seen from this cross section that a therapeutic
instrument comprised similarly to those in FIGS. 1-3, with an
actuator (12) attached to a catheter (20) and a needle (14)
disposed within the actuator.
Turning to FIGS. 11B and 11E, we see the same system as that in
FIGS. 11A and 11D, again where FIG. 11E is a view of the
cross-section along line 11E-11E from FIG. 11B. In FIGS. 11B and
11E, however, the actuator that has been filled with a fluid,
causing the actuator to unfurl and expand, and the needle aperture
to penetrate the media and into the adventitia where nerves are
located. After the needle penetrates to the adventitia, a plume (P)
that consists of either diagnositic agent such as radio-opaque
contrast medium or neuromodulating agent such as guanethidine or a
combination of the diagnostic and therapeutic agents is delivered
beyond the EEL and into the adventitia. The plume (P) begins to
migrate circumferentially and longitudinally within the adventitia
and begins to come into contact with the nerve fibers that run
through the adventitia. At this point, the physician may begin to
notice the therapeutic effects. Usually, the plume P that is used
to diagnose the presence of the injection and the location of the
injection is in the range from 10 to 100 .mu.l, more often around
50 .mu.l. The plume will usually indicate one of four outcomes: (1)
that the needle has penetrated into the adventitia and the plume
begins to diffuse in a smooth pattern around and along the outside
of the vessel, (2) that the plume follows the track of a sidebranch
artery, in which case the needle aperture has been located into the
sidebranch rather than in the adventitia, (3) that the plume
follows the track of the artery in which the catheter is located,
indicating that the needle has not penetrated the vessel wall and
fluid is escaping back into the main vessel lumen, or (4) that a
tightly constricted plume is forming and not diffusing
longitudinally or cyndrically around the vessel, indicating that
the needle aperture is located inward from the EEL and inside the
media or intima. The plume is therefore useful to the operating
physician to determine the appropriateness of continued injection
versus deflation and repositioning of the actuator at a new
treatment site.
In FIGS. 11C and 11F, where FIG. 11F is a cross-sectional view
across the line 11F-11F from FIG. 11C, one can see that after the
plume is used to diagnose the appropriate tissue location of
injection, further injection can be performed to surround the
vessel with the neuromodulating agent. The extent of the final
plume P* is usually fully circumferential around the artery and
usually travels longitudinally by at least 1 cm when the injection
volume is between 300 .mu.l and 3 ml. In many cases, less than
these volumes may be required in order to observe a therapeutic
benefit to the patient's hypertension. At this point, the
neuromodulating agent has penetrated the nerves around the entire
artery, blocking the transmission of nerve signals and thereby
creating chemical, neuromodulating, or biological denervation.
The following Experiments are offered by way of illustration, not
by way of limitation.
EXPERIMENTAL
Studies were performed in a normal porcine model to determine if
adventitial delivery of guanethidine could reduce kidney
norepinephrine (NE), a marker for successful denervation.
Successful denervation is well known to reduce blood pressure in
hypertensive patients.
Renal denervation evidenced by NE reduction: Guanethidine
monosulfate was diluted in 0.9% NaCl to a concentration of 12.5
mg/ml, then further diluted in iodinated contrast medium to a final
concentration of 10 mg/ml. This solution was injected using a
Mercator MedSystems Bullfrog Micro-Infusion Catheter (further
described in this application and detailed in FIG. 11A-F) into the
adventitia of both renal arteries, approximately halfway between
the aorta and the hilum of the kidney. The injection was monitored
with X-ray visualization of contrast medium to confirm adventitial
distribution, which was confirmed to carry the injectate
longitudinally and circumferentially around the artery, as well as
transversely into the perivascular tissue. No injection was made
into control animals, and historical controls from Connors 2004
were used as comparators.
Twenty-eight days after injection, kidneys and renal arteries were
harvested. Kidney samples were taken using the method established
by Connors 2004. Briefly, cortex tissue samples from the poles of
the kidneys were removed and sectioned into approximately 100 mg
segments. From each kidney, samples from each pole were pooled for
analysis. Renal arteries were perfusion fixed in 10% neutral
buffered formalin an submitted for histopathology.
Histology: Arteries appeared normal at 28 days, with no signs of
vascular toxicity. Perivascular indications of denervation were
apparent from lymphocyte, macrophage and plasma cell infiltration
into adventitial nerve bodies, with nerve degeneration
characterized by hypervacuolization and eosinophilia.
Radio-immunoassay: NE levels in renal cortex tissue revealed
average levels of 64 nanograms (ng) NE per gram (g) of renal
cortex. When compared to normal controls of 450 ng/g, this
represents a reduction in renal cortex NE of 86%. These data are
shown in FIG. 12.
Additional comparison can be made to the reduction in renal cortex
NE from surgical denervation, which Connors 2004 reported as 97%
and Krum 2008 reported as 94%. Furthermore, the reduction in kidney
NE reported with the use of radiofrequency catheter ablation of the
renal nerves has been reported as 86%. The radiofrequency method
has since been used in clinical trials and evidence has been shown
that the ablation of the nerves, resulting in reduced NE by 86%,
directly translates to reduced hypertension in patients, with
reports of systolic pressure reduction of 27 mmHg and diastolic
reduction of 17 mmHg, twelve months after treatment.
While the above is a complete description of the preferred
embodiments of the invention, various alternatives, modifications,
and equivalents may be used. Therefore, the above description
should not be taken as limiting the scope of the invention which is
defined by the appended claims.
* * * * *
References